Recent insights into the molecular pathophysiology of lipid droplet formation in hepatocytes

Sahini, Nishika; Borlak, Jürgen

doi:10.1016/j.plipres.2014.02.002

Cited by 104 publications

(101 citation statements)

References 319 publications

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“…Several characteristics of the NAFLD progression, such as hepatocyte ballooning, lead to activation of the stressMAPKinase signalling and previous studies have linked activation of the inflammatory stress-MAPKinases with progression of fatty liver disease (Sahini & Borlak 2014). In this sense, the activation of JNK as a main mechanism for the development of steatohepatitis has been largely described (Schattenberg et al 2006, Tuncman et al 2006, Singh et al 2009.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of stress-related pathways in HL K/K and WT mice Given the observed differences in inflammation and previous studies showing increased activation of the stress-MAPKinases associated with fatty liver disease (Sahini & Borlak 2014) the activation of these pathways was next evaluated. Protein lysate analysis of the p38 stress-pathway revealed increased (phospho)pp38 levels in the liver from HL K/K mice compared with those in WT mice ( Fig.…”

Section: Pancreas Characterisation In Hlmentioning

confidence: 99%

“…On the other hand, IR development, which alters carbohydrate and lipid metabolism, increases triglyceride accumulation in the liver (Samuel et al 2010, Samuel & Shulman 2012. Moreover, excess fat in adipocytes, which occurs in overweight and obesity, aggravates fatty liver disease by increasing the release of pro-inflammatory mediators such as MCP1, IL-6 and TNFa (Sahini & Borlak 2014). Of note, one of the main contributions to steatosis in NAFLD is an excess of circulating free fatty acids (FFA) and triglycerides which are also characteristics of the MetS and IR.…”

Section: Introductionmentioning

confidence: 99%

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Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Andrés‐Blasco¹,

Herrero-Cervera²,

Vinué³

et al. 2015

Journal of Endocrinology

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Metabolic syndrome and type 2 diabetes mellitus constitute a major problem to global health, and their incidence is increasing at an alarming rate. Non-alcoholic fatty liver disease, which affects up to 90% of obese people and nearly 70% of the overweight, is commonly associated with MetS characteristics such as obesity, insulin resistance, hypertension and dyslipidemia. In the present study, we demonstrate that hepatic lipase (HL)-inactivation in mice fed with a high-fat, high-cholesterol diet produced dyslipidemia including hypercholesterolemia, hypertriglyceridemia and increased non-esterified fatty acid levels. These changes were accompanied by glucose intolerance, pancreatic and hepatic inflammation and steatosis. In addition, compared with WT mice, HL K/K mice exhibited enhanced circulating MCP1 levels, monocytosis and higher percentage of CD4CTh17C cells. Consistent with increased inflammation, livers from HL K/K mice had augmented activation of the stress SAPK/JNK-and p38-pathways compared with the activation levels of the kinases in livers from WT mice. Analysis of HL K/K and WT mice fed regular chow diet showed dyslipidemia and glucose intolerance in HL K/K mice without any other changes in inflammation or hepatic steatosis. Altogether, these results indicate that dyslipidemia induced by HL-deficiency in combination with a high-fat, high-cholesterol diet promotes hepatic steatosis and inflammation in mice which are, at least in part, mediated by the activation of the stress SAPK/JNK-and p38-pathways. Future studies are warranted to asses the viability of therapeutic strategies based on the modulation of these kinases to reduce hepatic steatosis associated to lipase dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Pancreas Characterisation In Hlmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Andrés‐Blasco¹,

Herrero-Cervera²,

Vinué³

et al. 2015

Journal of Endocrinology

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“…Lipid droplets have recently garnered much attention, particularly in the last decade, as abnormal quantity of lipid droplets has been linked to several metabolic diseases [18,19]. D), pCE-puro 3xFLAG-mALDH3B2 (C), pCE-puro 3xFLAG-mALDH3B3 (C), pCE-puro 3xFLAG-mALDH3B1-C462S (D), pCE-puro 3xFLAG-mALDH3B1-C463S (D), or pCE-puro 3xFLAG-mALDH3B1-C462/463S (D) plasmid.…”

Section: Discussionmentioning

confidence: 99%

“…Lipid droplets store abundant triglycerides for membrane synthesis and as an energy supply, and imbalances of lipid droplets and fat storage are associated with several metabolic diseases [18,19]. The structure of lipid droplets is unique in that they consist of a hydrophobic core of neutral lipids surrounded by a monolayer of phospholipids, mainly phosphatidylcholine [20].…”

Section: Introductionmentioning

confidence: 99%

Mouse aldehyde dehydrogenase ALDH3B2 is localized to lipid droplets via two C-terminal tryptophan residues and lipid modification

Kitamura

Takagi

Naganuma

et al. 2014

Biochemical Journal

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Short title: Lipid droplet localization of ALDH3B2Summary statement: The mouse aldehyde dehydrogenases ALDH3B2 and ALDH3B3 exhibit similar substrate specificity but distinct intracellular localization (ALDH3B2, lipid droplets; ALDH3B3, plasma membrane). The C-terminal prenylation and two Trp residues are important for the lipid droplet localization of ALDH3B2.2 ABSTRACT Aldehyde dehydrogenases (ALDHs) catalyze the conversion of toxic aldehydes to non-toxic carboxylic acids. Of the 21 ALDHs in mice, it is the ALDH3 family members (ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2, and ALDH3B3) that are responsible for the removal of lipid-derived aldehydes. However, ALDH3B2 and ALDH3B3 have yet to be characterized.Here, we examined the enzyme activity, tissue distribution, and subcellular localization of ALDH3B2 and ALDH3B3. Both were found to exhibit broad substrate preferences from medium-chain to long-chain aldehydes, resembling ALDH3A2 and ALDH3B1. Although ALDH3B2 and ALDH3B3 share extremely high sequence similarity, their localizations differed, with ALDH3B2 found in lipid droplets and ALDH3B3 localized to the plasma membrane. Both ALDH3B2 and ALDH3B3 were modified by prenylation at their C-termini; this modification greatly influenced their membrane localization and enzymatic activity toward hexadecanal. We found that their C-terminal regions, particularly the two Trp residues (Trp462 and Trp469) of ALDH3B2 and the two Arg residues (Arg462 and Arg463) of ALDH3B3, were important for the determination of their specific localization. Abnormal quantity and perhaps quality of lipid droplets are implicated in several metabolic diseases. We speculate that ALDH3B2 acts to remove lipid-derived aldehydes in lipid droplets generated via oxidative stress as a quality control mechanism.

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Lipidomics on Cell Organelle and Subcellular Membranes

Han

2016

Lipidomics

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Recent insights into the molecular pathophysiology of lipid droplet formation in hepatocytes

Cited by 104 publications

References 319 publications

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Mouse aldehyde dehydrogenase ALDH3B2 is localized to lipid droplets via two C-terminal tryptophan residues and lipid modification

Lipidomics on Cell Organelle and Subcellular Membranes

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